public assessment report pantodia 20mg and 40 mg gastro

PAR Pantodia/Dialoc 20mg and 40mg Gastro-resistant Tablets UK/H/1802-3/01-02/DC

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Public Assessment Report

Decentralised Procedure

Pantodia 20mg and 40 mg Gastro-resistant

Tablets

Dialoc 20mg and 40mg Gastro-resistant Tablets

Pantoprazole sodium sesquihydrate

UK/H/1802-3/01-02/DC

UK licence no: PL 32652/0001-4

Applicant: DiaMed GmbH


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LAY SUMMARY On the 24th May 2010 the MHRA granted DiaMed GmbH Marketing Authorisations (licences) for the medicinal products Pantodia/Dialoc 20mg and 40mg Gastro-resistant Tablets. These are prescription-only medicines (POM). Pantoprazole belongs to a group of medicines called proton pump inhibitors which work by reducing the amount of acid your stomach makes.

Pantodia/Dialoc 20 mg is used: • To treat mild oesophageal disease due to reflux of acid from the stomach

(reflux disease) and associated symptoms such as heartburn, acid regurgitation and pain on swallowing.

• For the long-term treatment and the prevention of oesophageal inflammation (reflux oesophagitis) and its relapse.

• To prevent duodenal (small bowel) and stomach ulcers caused by non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk, who need long-term treatment with these medicines.

Pantodia/Dialoc 40 mg is used: • in the treatment of moderate to severe forms of reflux oesophagitis (an

inflammation of your oesophagus, or gullet, caused by the regurgitation of stomach acid).

• in treating an infection with a bacterium called Helicobacter pylori in patients with duodenal ulcers and stomach ulcers in combination with two antibiotics (Eradication therapy). The aim is to get rid of the bacteria and so reduce the likelihood of these ulcers returning.

• in the treatment of duodenal (small bowel) and stomach ulcers • to treat Zollinger-Ellison syndrome and other conditions producing too

much acid in the stomach. No new or unexpected safety concerns arose from these applications and it was therefore judged that the benefits of taking Pantodia/Dialoc outweigh the risks; hence Marketing Authorisations have been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflet 3 Module 4: Labelling Page 57 Module 5: Scientific Discussion Page 73 I Introduction II. Quality aspects III. Non-clinical aspects IV. Clinical aspects V. Overall conclusion and Benefit-Risk Assessment Module 6 Steps taken after initial procedure


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Module 1 Product Name

Pantodia/Dialoc 20mg and 40mg Gastro-resistant Tablets

Type of Application

Generic, Article 10.1

Active Substance

Pantoprazole sodium sesquihydrate

Form

Gastro-resistant Tablets

Strength

20mg and 40mg

MA Holder

DiaMed GmbH, Kaiser-Wilhelm-ring 4-6, 48145 Munster Germany

RMS

UK

CMS

UK/H/1802/01-02/DC: Poland, Romania, and Slovenia UK/H/1803/01-02/DC: Austria, Belgium, Denmark, Finland, The Netherlands, Norway, Poland and Sweden

Procedure Number

UK/H/1802-3/01-02/DC

Timetable

Day 210 – 21st April 2010


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Module 2

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Pantodia 20 mg Gastro-resistant tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 20 mg pantoprazole (as pantoprazole sodium sesquihydrate 22.55 mg) Excipient: Lactose 18.1 mg For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Gastro-resistant tablet Yellow to ochre, elongated coated tablet

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

• For the treatment of mild reflux disease and related symptoms (e.g. heartburn, acid regurgitation and pain on swallowing).

• For the long-term treatment and prevention of relapse in reflux oesophagitis.

• To prevent peptic ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).

4.2 Posology and method of administration

Method of administration Pantodia 20 mg should be swallowed whole with water before a meal. The tablets should not be chewed or crushed. Adults and adolescents 12 years of age and above: Mild reflux disease and related symptoms (e.g. heartburn, acid regurgitation and pain on swallowing): The recommended dose is one Pantodia 20 mg gastro-resistant tablet per day. Symptom relief is generally achieved within 2 - 4 weeks, and a 4-week treatment period is usually required for healing of associated oesophagitis. If still symptomatic, healing will normally be achieved with a further 4-weeks’ treatment. Recurrent symptoms can be controlled by taking 20 mg once a day as required (on-demand therapy). A switch to continuous therapy may need to be considered if satisfactory symptom control cannot be maintained with on-demand treatment. Long-term therapy and preventing relapses of reflux oesophagitis. For long-term therapy, a maintenance dose of 20 mg pantoprazole daily (one Pantodia 20 mg tablet per day is recommended). If relapse occurs, the dosage can be increased to 40 mg pantoprazole per day. If required, Pantodia 40 mg is available. After the oesophageal inflammation has been cured the dose can be reduced to 20 mg pantoprazole again. Adults Prevention of peptic ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require continuous NSAID therapy. The recommended dose is one Pantodia 20 mg gastro-resistant tablet per day.


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Patients with hepatic impairment: Patients with severe hepatic impairment should not take more than 20 mg pantoprazole a day (see section 4.4). In these patients, liver function tests should be monitored during treatment. If a rise in liver enzymes is observed, treatment with pantoprazole should be discontinued. Patients with reduced kidney function: A daily dose of 40mg pantoprazole should not be exceeded. Elderly patients: A daily dose of 40mg pantoprazole should not be exceeded. Children below 12 years of age: There is no experience in the use of pantoprazole in children. Pantoprazole should therefore not be used in children.

4.3 Contraindications

Pantodia 20 mg should not be taken under the following circumstances: Hypersensitivity to pantoprazole or to any of the excipients (see section 6.1)

Pantoprazole, like other proton pump inhibitors, should not be administered with atazanavir (see section 4.5).

4.4 Special warnings and precautions for use

Pantoprazole is not intended for the treatment of the gastrointestinal symptoms accompanying functional dyspepsia. Patients with severe liver damage should have their liver function tested regularly when being treated with pantoprazole, especially if it is a long-term course of treatment. If their liver enzyme levels rise they should stop taking Pantodia 20 mg. Pantodia 20 mg should only be used to prevent peptic ulcers caused by non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) if the patient needs continuous treatment with these medicines and has an increased risk of gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. old age (> 65), previous peptic ulcers or bleeding in the upper gastrointestinal tract. As with all drugs which inhibit gastric acid production, (cyanocobalamin) malabsorption due to hypochlorhydria or achlorhydria may occur. This should be considered in patients on long-term therapy who have reduced vitamin B12 body stores or risk factors for reduced B12 absorption or in those who exhibit signs or symptoms of B12 deficiency. Patients should be regularly monitored if they take this medication for a long period of time, especially if their course of treatment lasts more than a year. If the patient exhibits worrying signs or symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or blood in their stool and/or melena) or if a stomach ulcer is suspected or has been confirmed, malignant disease of the oesophagus or stomach should be excluded since treatment with pantoprazole can mask the symptoms of malignancy and thus delay diagnosis. Decreased gastric acidity due to any means – including proton pump inhibitors – increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. If the symptoms persist after 4 weeks despite adequate treatment, further tests should be considered. Pantoprazole is not intended for the treatment of the gastrointestinal symptoms accompanying functional dyspepsia.


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There is no experience in children. Patients with rare hereditary galactose intolerance, lactase deficiency or glucose galactose malabsorption should not take Pantodia 20 mg. This medicinal product contains 1.34 mg sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Studies with other proton pump inhibitors have shown that the bioavailability of atazanavir is significantly reduced when it is used concomitantly with proton pump inhibitors. Therefore the use of pantoprazole is contraindicated during atazanavir treatment. Pantodia 20 mg can reduce the absorption of medicines, whose bioavailability is dependent on pH level (e.g. ketoconazole and itraconazole). Pantoprazole is metabolised in the liver by the cytochrome P450 enzyme system. Interaction with other medicines such as substances, which are broken down by the same enzyme system, cannot be ruled out. However, no clinically significant interactions were found in targeted studies with a range of such medicines or compounds, such as carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and oral contraceptives. Although no interactions were found in clinical pharmacokinetic studies when phenprocoumon or warfarin were taken concomitantly, a few isolated post-marketing reports of changes in prothrombin time / INR have been reported. It is therefore recommended that prothrombin time / INR are monitored in patients being treated with concomitant coumarin anticoagulants after initiation, termination or during irregular use of pantoprazole. There were also no interactions with concomitantly administered antacids.

4.6 Pregnancy and lactation

Clinical experience with pregnant women is limited. In animal experimental reproduction studies mild fetotoxicity was observed with doses above 5 mg/kg. There is no information on the transfer of pantoprazole into breast milk in humans. If a patient is pregnant or breast-feeding a child, she should only take pantoprazole if the benefit of the treatment for her is higher than the potential risk for her unborn child or baby.

4.7 Effects on ability to drive and use machines

There are no known effects on the ability to drive or use machines. However uncommon side-effects such as dizziness or blurred vision have been reported (see section 4.8) if affected the patient should refrain from driving or using machines.

4.8 Undesirable effects

Common ≥1/100 to <1/10 Uncommon ≥1/1,000 to <1/100 Rare ≥1/10,000 to <1/1,000 Very rare <1/10,000, including isolated reports

Frequency common uncommon rare very rare Organ system Blood and the lymphatic system disorders

Leucopenia, thrombocytopenia

Immune system disorders

Hypersensitivity manifesting as pruritus and skin rash

Anaphylactic reactions including anaphylactic shock

Psychiatric Depression,


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disorders hallucination, disorientation and confusion especially in predisposed patients, as well as the aggravation of such symptoms

Nervous system disorders

Headache Dizziness, visual disturbance (blurred vision)

Gastrointestinal disorders

Upper abdominal pain, diarrhoea, constipation, flatulence

Nausea, vomiting, Dry mouth

Hepatobiliary disorders

Severe hepatocellular damage leading to jaundice with or without hepatic failure

Skin and sub-cutaneous tissue disorders

Hypersensitivity reactions such as pruritus and skin rash

Urticaria, angioedema, severe skin reactions such as Stevens-Johnson syndrome, erythema multiforme, Lyell's syndrome, photosensitivity

Musculoskeletal, connective tissue disorders

Arthralgia Myalgia

Renal and urinary disorders

Interstitial nephritis

General disorders and administration site conditions

Peripheral edema subsiding after termination of therapy

4.9 Overdose

There are no recognised symptoms of overdose and doses up to 240 mg i.v., administered over 2 minutes, have been well tolerated. If overdose is accompanied by clinical signs or symptoms indicative of toxicity, standard supportive therapy should be initiated.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Proton pump inhibitors ATC Code: A02BC02 Pantoprazole is a substituted benzimidazole, which inhibits gastric juice secretion through specific reactions with proton pumps in the parietal cells. Pantoprazole is converted to its active form in the acidic channel of the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and acts on both basal and stimulated gastric juice secretion. Most patients are symptom-free within 2 weeks. Like with other proton pump inhibitors and H2 receptor blockers, treatment with pantoprazole reduces levels of gastric juice, which causes a rise in gastrin in relation to the acid reduction. The rise in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can affect


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acid secretion independently of stimulation by other substances (acetylcholine, histamine and gastrin). Pantoprazole has the same effect when administered orally and intravenously. Fasting gastrin levels rise with pantoprazole. If pantoprazole is only used for a short term therapy, it doesn’t usually exceed the upper limit of normal. If pantoprazole is taken over a long period of time, gastrin levels can double. An excessive increase, however, occurs only in isolated cases. With long-term treatment a mild to moderate increase of specific endocrine (ECL = enterochromaffin-like) cells in the stomach occurs in a minority of patients (simple to adenomatoid hyperplasia). However, to date, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids, such as were reported in animal trials (see section 5.3), have not been observed in studies in humans.

5.2 Pharmacokinetic properties

General pharmacokinetics Pantoprazole is rapidly absorbed and the maximum serum concentration of around 1 - 1.5 µg/ml is reached after an average of 2.0 – 2.5 hours and remains constant on multiple dosing. The volume of distribution is around 0.15 l/kg, and clearance is around 0.1 l/h/kg. The terminal elimination half-life is about 1 hour though a small number of subjects show slower elimination. Because of the mechanism of binding of pantoprazole to the proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of therapeutic action (inhibition of acid secretion). For both oral and intravenous administration, the pharmacokinetics remain constant after single and multiple dosing and are linear over the dose range 10 – 80 mg. Serum protein binding of pantoprazole is around 98%. Pantoprazole is virtually entirely metabolised by the liver. Most metabolites (around 80 %) are eliminated in the kidneys, and the rest are excreted in faeces. The main metabolite in serum and urine is desmethyl-pantoprazole conjugated with sulphate. The half-life of this main metabolite (about 1.5 h) is not much longer than that of pantoprazole. Bioavailability Pantoprazole is completely absorbed after oral administration. The bioavailability of the tablet being around 77 %. AUC, maximum serum concentration and oral bioavailability are unaffected by food, though lag-time may be increased. Special patient groups No dose reduction is required when pantoprazole is given to patients with reduced kidney function (including dialysis patients) although a daily dose of 40 mg should not be exceeded (see section 4.2). The half-life is not prolonged. Pantoprazole is only dialysed to a very small extent. Although the main metabolite shows a moderately increased half-life (2 – 3 hours), there is no accumulation with this rapid elimination. In patients with liver cirrhosis (Child A and Child B classification) the half-life increases to 3 - 6 hours and the AUC increases by a factor of 3 – 5. However, the maximum serum concentration only increased by a factor of 1.3 compared to in those with normal hepatic function. A relative slight increase of AUC and Cmax in elderly patients is of no clinical relevance.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. In a 2-year carcinogenicity study on rats, neuroendocrine tumours were found. Squamous cell papilloma also appeared in the rats’ gastroesophageal vestibule. The mechanism, which is based on stomach carcinoids forming due to substituted benzimidazole, was studied


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immediately and the conclusion was that it is an indirect mechanism due to the significantly increased serum gastrin level in rats when it is administered chronically and in high doses. A higher rate of liver tumours was observed in rats (only in one study) and female mice in the 2-year studies, which can be interpreted as a consequence of pantoprazole’s high metabolic rate in the liver. In one 2-year study a smaller rise in neoplasms in the rats’ thyroid gland was observed in the highest dose group (200 mg/kg). The appearance of these neoplasms is related to thyroxin being broken down differently in the rats’ liver due to pantoprazole. On the basis of the low therapeutic dose in humans, no side effects on the thyroid glands are expected. From mutagenicity studies, cell transformation tests and a DNA binding study it is concluded that pantoprazole has no genotoxic potential. Tests have revealed no evidence of impaired fertility or teratogenic effects. The placental transfer of pantoprazole was examined in the rats. It increases with progressive pregnancy. Therefore the concentration is elevated in the fetus just before it is born.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Tablet Core: microcrystalline cellulose (E460i) lactose monohydrate croscarmellose sodium colloidal anhydrous silica magnesium stearate Colour coating: polyvinyl alcohol macrogol 3350 titanium dioxide (E171) talc (E553b) iron oxide yellow (E172) quinoline yellow aluminium lake (E104) Gastro-resistant coating: methacryl acid-ethyl acrylate copolymer sodium lauryl sulphate polysorbate 80 triethyl citrate (E1505) talc (E553b)

6.2 Incompatibilities

Not applicable 6.3 Shelf life

Blister: 2 years. Tablet container: 3 years. Shelf life after first opening: 28 days.

6.4 Special precautions for storage

Blister: Do not store above 30 °C. Tablet container: Do not store above 25 °C.

6.5 Nature and contents of container Blister: Aluminium-Aluminium foil blister Original packages of 7, 14, 28 or 56 gastro-resistant tablets. Tablet container: HDPE bottles with HDPE or PP screw cap closure with desiccant. Original packages of 7, 14, 28 or 50 gastro-resistant tablets. Not all pack sizes may be marketed.


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6.6 Special precautions for disposal

No special requirements. 7 MARKETING AUTHORISATION HOLDER

DiaMed GmbH Kaiser-Wilhelm-Ring 4-6 48145 Münster Germany

8 MARKETING AUTHORISATION NUMBER(S)

PL 32652/0001 9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/05/2010 10 DATE OF REVISION OF THE TEXT

24/05/2010


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1 NAME OF THE MEDICINAL PRODUCT Pantodia 40 mg Gastro-resistant tablets


Each gastro-resistant tablet contains 40 mg pantoprazole (as pantoprazole sodium sesquihydrate 45.1 mg) Excipients: Lactose 36.2 mg, tartrazine For a full list of excipients, see section 6.1.


Gastro-resistant tablet Pale yellow to ochre, elongated coated tablet


For relieving the symptoms of, and for the short-term treatment of, gastrointestinal diseases which require a reduction in gastric acid secretion.

• Moderate and severe reflux oesophagitis

• Duodenal ulcer

• Gastric ulcer

• Eradication of Helicobacter pylori, in combination with antibiotic therapy, in patients with peptic ulceration

• Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid.


Method of administration Pantodia 40 mg should be swallowed whole with water before a meal. The tablets should not be chewed or crushed. Adults and adolescents 12 years of age and above Moderate and severe reflux oesophagitis: The recommended dosage is 40 mg pantoprazole daily. In some cases this may be doubled, especially when there has been no response to other treatment. A four-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further four weeks. Adults Gastric and duodenal ulcer: The recommended dosage is 40 mg pantoprazole daily. In some cases this may be doubled, especially when there has been no response to other treatment. Duodenal ulcers generally heal within two weeks. If a two-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks. A four week treatment period is usually required for the treatment of gastric ulcers and reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further four weeks. Eradication of Helicobacter pylori (H. pylori): The recommended dose is 40 mg pantoprazole twice daily, in combination with one of the following three antibiotic regimens: a) Amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily. b) Clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily


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c) Amoxicillin 1000 mg twice daily + metronidazole 500 mg twice daily The second pantoprazole tablet should be taken before the evening meal. Combination therapy should be continued for seven days in most cases but may sometimes be required for up to 14 days. Zollinger-Ellison Syndrome and other hypersecretory conditions: For long-term therapy of Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid, the recommended initial dose is 80 mg (2 tablets Pantodia 40 mg) per day. The dosage can subsequently be adjusted individually according to the determination of gastric acid secretion. For doses of more than 80 mg per day, the dose should be divided and given twice daily. A temporary increase in dose to more than 160 mg pantoprazole per day is possible. However, the increase should only last as long as required to sufficiently control acid secretion. With Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid, the period of treatment is not restricted and should continue as long as clinically required. Elderly A daily dose of 40 mg pantoprazole should not be exceeded unless for the eradication treatment of H. pylori in which case a regimen including pantoprazole 40 mg twice daily should be used (see above). Patients with renal impairment A daily dose of 40 mg pantoprazole should not be exceeded. For this reason the H.pylori eradication regimen is not recommended in these patients (see section 4.3). Patients with hepatic impairment The dose should be reduced to 40 mg pantoprazole every other day in patients with severe liver insufficiency and for this reason the H. pylori eradication regimen is not recommended in these patients (see section 4.3). In addition, liver function tests should be monitored in these patients during therapy with Pantodia 40 mg and treatment discontinued if an increase in liver enzymes is observed. Children below 12 years of age There is no experience in the use of pantoprazole in children. Therefore pantoprazole tablets should not be used in children.


Pantodia 40 mg should not be taken under the following circumstances: − Hypersensitivity to pantoprazole or to any of the excipients (see section 6.1)

− in combination therapy for eradication of Helicobacter pylori in patients with moderate to severe hepatic or renal dysfunction, since currently no data is available on the efficacy and safety of pantoprazole in combination treatment of these patients.

− Pantoprazole, like other proton pump inhibitors, should not be administered with atazanavir (see section 4.5).

− Pantoprazole should not be used in combination therapy for the eradication of H. pylori in patients with moderate to severe hepatic or renal dysfunction since there are currently no relevant efficacy and safety data in relation to this.


Pantoprazole is not intended for the treatment of gastrointestinal symptoms accompanying functional dyspepsia. The Summaries of Product Characteristics for each medication should be observed for combination therapy.


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For patients with Zollinger-Ellison syndrome and other diseases associated with abnormal overproduction of gastric acid requiring long-term treatment, pantoprazole, as with other acid-blocking drugs, may reduce the absorption of Vitamin B12 (cyanocobalamin) due to hypochlorhydria or achlorhydria. This should be considered in patients on long-term therapy who have reduced B12 body stores or risk factors for reduced vitamin B12 absorption or in those who exhibit signs or symptoms of B12 deficiency. If the patient exhibits worrying signs or symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or blood in the stool/melena) or if a stomach ulcer is suspected or has been confirmed, malignant disease of the oesophagus or stomach should be excluded. This is because treatment with pantoprazole may mask the symptoms of malignancy and thus delay diagnosis. Diagnoses of peptic oesophagitis should be performed endoscopically. There are no data currently available on the use of pantoprazole in children. Patients with rare hereditary galactose intolerance, lactase deficiency or glucose galactose malabsorption should not take Pantodia 40 mg. This product contains tartrazine, which may cause allergic reactions. This medicinal product contains 2.68 mg sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.


Studies with other proton pump inhibitors have shown that the bioavailability of atazanavir is significantly reduced when it is used concomitantly with proton pump inhibitors. Therefore the use of pantoprazole is contraindicated during atazanavir treatment. Pantodia 40 mg can reduce the absorption of medicines, whose bioavailability is dependent on pH level (e.g. ketoconazole and itraconazole). Pantoprazole is metabolised in the liver by the cytochrome P450 enzyme system. Interaction with other medicines such as substances, which are broken down by the same enzyme system, cannot be ruled out. However, no clinically significant interactions were found in targeted studies with a range of such medicines or compounds, such as carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and oral contraceptives. No clinically relevant interactions have been observed in human pharmacokinetic studies with clarithromycin, metronidazole or amoxicillin. Although no interactions were found in clinical pharmacokinetic studies when phenprocoumon or warfarin were taken concomitantly, a few isolated post-marketing reports of changes in prothrombin time / INR have been reported. It is therefore recommended that prothrombin time / INR are monitored in patients being treated with concomitant coumarin anticoagulants after initiation, termination or during irregular use of pantoprazole. There were also no interactions with concomitantly administered antacids.





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There are no known effects on the ability to drive or use machines. However, uncommon side-effects such as dizziness or blurred vision have been reported (see section 4.8) if affected the patient should refrain from driving or using machines.








Psychiatric disorders Depression, hallucination, disorientation and confusion especially in predisposed patients, as well as the aggravation of such symptoms












Arthralgia Myalgia





4.9 Overdose


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Pharmacotherapeutic group: Proton pump inhibitors ATC Code: A02BC02 Pantoprazole is a substituted benzimidazole, which inhibits gastric juice secretion through specific reactions with proton pumps in the parietal cells. Pantoprazole is converted to its active form in the acidic channel of the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and acts on both basal and stimulated gastric juice secretion. Most patients are symptom-free within 2 weeks. Like with other proton pump inhibitors and H2 receptor blockers, treatment with pantoprazole reduces levels of gastric juice, which causes a rise in gastrin in relation to the acid reduction. The rise in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can affect acid secretion independently of stimulation by other substances (acetylcholine, histamine and gastrin). Pantoprazole has the same effect when administered orally and intravenously. Fasting gastrin levels rise with pantoprazole. If pantoprazole is only used for a short term therapy, it usually doesn’t exceed the upper limit of normal. If pantoprazole is taken over a long period of time, gastrin levels can double. An excessive increase, however, occurs only in isolated cases. With long-term treatment a mild to moderate increase of specific endocrine (ECL = enterochromaffin-like) cells in the stomach occurs in a minority of patients (simple to adenomatoid hyperplasia). However, to date, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids, such as were reported in animal trials (see section 5.3), have not been observed in studies in humans.


General pharmacokinetics Pantoprazole is rapidly absorbed and the maximum serum concentration of around 2 - 3 µg/ml is reached after an average of 2.0 – 2.5 hours. The volume of distribution is around 0.15 l/kg, and clearance is around 0.1 l/h/kg. The terminal elimination half-life is about 1 hour though a small number of subjects show slower elimination. Because of the mechanism of binding of pantoprazole to the proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of therapeutic action (inhibition of acid secretion). For both oral and intravenous administration, the pharmacokinetics remain constant after single and multiple dosing and are linear over the dose range 10 – 80 mg. Serum protein binding of pantoprazole is around 98 %. Pantoprazole is virtually entirely metabolised by the liver. Most metabolites (around 80 %) are eliminated in the kidneys, and the rest are excreted in faeces. The main metabolite in serum and urine is desmethyl-pantoprazole conjugated with sulphate. The half-life of this main metabolite (about 1.5 h) is not much longer than that of pantoprazole. Bioavailability Pantoprazole is completely absorbed after oral administration. The bioavailability of the tablet being around 77 %. AUC, maximum serum concentration and oral bioavailability are unaffected by food, though lag-time may be increased. Special patient groups


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No dose reduction is required when pantoprazole is given to patients with reduced kidney function (including dialysis patients) although a daily dose of 40 mg should not be exceeded (see section 4.2). The half-life is not prolonged. Pantoprazole is only dialysed to a very small extent. Although the main metabolite shows a moderately increased half-life (2 – 3 hours), there is no accumulation with this rapid elimination. In patients with liver cirrhosis (Child A and Child B classification) the half-life increases to 3 - 6 hours and the AUC increases by a factor of 3 – 5. However, the maximum serum concentration only increased by a factor of 1.3 compared to in those with normal hepatic function. A relative slight increase of AUC and Cmax in elderly patients is of no clinical relevance.


Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. In a 2-year carcinogenicity study on rats, neuroendocrine tumours were found. Squamous cell papilloma also appeared in the rats’ gastroesophageal vestibule. The mechanism, which is based on stomach carcinoids forming due to substituted benzimidazole, was studied immediately and the conclusion was that it is an indirect mechanism due to the significantly increased serum gastrin level in rats when it is administered chronically and in high doses. A higher rate of liver tumours was observed in rats (only in one study) and female mice in the 2-year studies, which can be interpreted as a consequence of pantoprazole’s high metabolic rate in the liver. In one 2-year study a smaller rise in neoplasms in the rats’ thyroid gland was observed in the highest dose group (200 mg/kg). The appearance of these neoplasms is related to thyroxin being broken down differently in the rats’ liver due to pantoprazole. On the basis of the low therapeutic dose in humans, no side effects on the thyroid glands are expected. From mutagenicity studies, cell transformation tests and a DNA binding study it is concluded that pantoprazole has no genotoxic potential. Tests have revealed no evidence of impaired fertility or teratogenic effects. The placental transfer of pantoprazole was examined in the rats. It increases with progressive pregnancy. Therefore the concentration is elevated in the fetus just before it is born.


Tablet Core: microcrystalline cellulose (E460i) lactose monohydrate croscarmellose sodium colloidal anhydrous silica magnesium stearate Colour coating: polyvinyl alcohol macrogol 3350 titanium dioxide (E171) talc (E553b) iron oxide yellow (E172) tartrazine aluminium lake (E102) Gastro-resistant coating: methacryl acid-ethyl acrylate copolymer sodium lauryl sulphate polysorbate 80 triethyl citrate (E1505)


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talc (E553b) 6.2 Incompatibilities





6.5 Nature and contents of container

Blister: Aluminium-Aluminium foil blister Original packages of 7, 14, 28 or 56 gastro-resistant tablets. Tablet container: HDPE bottles with HDPE or PP screw cap closure with desiccant. Original packages of 7, 14, 28 or 50 gastro-resistant tablets. Not all pack sizes may be marketed.


No special requirements. 7 MARKETING AUTHORISATION HOLDER




24/05/2010

10 DATE OF REVISION OF THE TEXT 24/05/2010


19

1 NAME OF THE MEDICINAL PRODUCT Dialoc 20 mg Gastro-resistant tablets


Each gastro-resistant tablet contains 20 mg pantoprazole (as pantoprazole sodium sesquihydrate 22.55 mg) Excipient: Lactose 18.1 mg For a full list of excipients, see section 6.1.


Gastro-resistant tablet Yellow to ochre, elongated coated tablet


• For the treatment of mild reflux disease and related symptoms (e.g. heartburn, acid regurgitation and pain on swallowing).

• For the long-term treatment and prevention of relapse in reflux oesophagitis.

• To prevent peptic ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk with a need for continuous NSAID treatment (see section 4.4).


Method of administration Dialoc 20 mg should be swallowed whole with water before a meal. The tablets should not be chewed or crushed. Adults and adolescents 12 years of age and above: Mild reflux disease and related symptoms (e.g. heartburn, acid regurgitation and pain on swallowing): The recommended dose is one Dialoc 20 mg gastro-resistant tablet per day. Symptom relief is generally achieved within 2 - 4 weeks, and a 4-week treatment period is usually required for healing of associated oesophagitis. If still symptomatic, healing will normally be achieved with a further 4-weeks’ treatment. Recurrent symptoms can be controlled by taking 20 mg once a day as required (on-demand therapy). A switch to continuous therapy may need to be considered if satisfactory symptom control cannot be maintained with on-demand treatment. Long-term therapy and preventing relapses of reflux oesophagitis. For long-term therapy, a maintenance dose of 20 mg pantoprazole daily (one Dialoc 20 mg tablet per day is recommended). If relapse occurs, the dosage can be increased to 40 mg pantoprazole per day. If required, Dialoc 40 mg is available. After the oesophageal inflammation has been cured the dose can be reduced to 20 mg pantoprazole again. Adults Prevention of peptic ulcers caused by non-selective non-steroidal anti-inflammatory drugs (NSAIDs) in patients at risk who require continuous NSAID therapy. The recommended dose is one Dialoc 20 mg gastro-resistant tablet per day. Patients with hepatic impairment:


20

Patients with severe hepatic impairment should not take more than 20 mg pantoprazole a day (see section 4.4). In these patients, liver function tests should be monitored during treatment. If a rise in liver enzymes is observed, treatment with pantoprazole should be discontinued. Patients with reduced kidney function: A daily dose of 40mg pantoprazole should not be exceeded. Elderly patients: A daily dose of 40mg pantoprazole should not be exceeded. Children below 12 years of age: There is no experience in the use of pantoprazole in children. Pantoprazole should therefore not be used in children.


Dialoc 20 mg should not be taken under the following circumstances: − Hypersensitivity to pantoprazole or to any of the excipients (see section 6.1)



Pantoprazole is not intended for the treatment of the gastrointestinal symptoms accompanying functional dyspepsia. Patients with severe liver damage should have their liver function tested regularly when being treated with pantoprazole, especially if it is a long-term course of treatment. If their liver enzyme levels rise they should stop taking Dialoc 20 mg. Dialoc 20 mg should only be used to prevent peptic ulcers caused by non-selective, non-steroidal anti-inflammatory drugs (NSAIDs) if the patient needs continuous treatment with these medicines and has an increased risk of gastrointestinal complications. The increased risk should be assessed according to individual risk factors, e.g. old age (> 65), previous peptic ulcers or bleeding in the upper gastrointestinal tract. As with all drugs which inhibit gastric acid production, (cyanocobalamin) malabsorption due to hypochlorhydria or achlorhydria may occur. This should be considered in patients on long-term therapy who have reduced vitamin B12 body stores or risk factors for reduced B12 absorption or in those who exhibit signs or symptoms of B12 deficiency. Patients should be regularly monitored if they take this medication for a long period of time, especially if their course of treatment lasts more than a year. If the patient exhibits worrying signs or symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or blood in their stool and/or melena) or if a stomach ulcer is suspected or has been confirmed, malignant disease of the oesophagus or stomach should be excluded since treatment with pantoprazole can mask the symptoms of malignancy and thus delay diagnosis. Decreased gastric acidity due to any means – including proton pump inhibitors – increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with acid-reducing drugs may lead to a slightly increased risk of gastrointestinal infections, such as Salmonella and Campylobacter. If the symptoms persist after 4 weeks despite adequate treatment, further tests should be considered. Pantoprazole is not intended for the treatment of the gastrointestinal symptoms accompanying functional dyspepsia. There is no experience in children.


21

Patients with rare hereditary galactose intolerance, lactase deficiency or glucose galactose malabsorption should not take Dialoc 20 mg. This medicinal product contains 1.34 mg sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.


Studies with other proton pump inhibitors have shown that the bioavailability of atazanavir is significantly reduced when it is used concomitantly with proton pump inhibitors. Therefore the use of pantoprazole is contraindicated during atazanavir treatment. Dialoc 20 mg can reduce the absorption of medicines, whose bioavailability is dependent on pH level (e.g. ketoconazole and itraconazole). Pantoprazole is metabolised in the liver by the cytochrome P450 enzyme system. Interaction with other medicines such as substances, which are broken down by the same enzyme system, cannot be ruled out. However, no clinically significant interactions were found in targeted studies with a range of such medicines or compounds, such as carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and oral contraceptives. Although no interactions were found in clinical pharmacokinetic studies when phenprocoumon or warfarin were taken concomitantly, a few isolated post-marketing reports of changes in prothrombin time / INR have been reported. It is therefore recommended that prothrombin time / INR are monitored in patients being treated with concomitant coumarin anticoagulants after initiation, termination or during irregular use of pantoprazole. There were also no interactions with concomitantly administered antacids.




There are no known effects on the ability to drive or use machines. However uncommon side-effects such as dizziness or blurred vision have been reported (see section 4.8) if affected the patient should refrain from driving or using machines.








Psychiatric disorders

Depression, hallucination, disorientation and


22

confusion especially in predisposed patients, as well as the aggravation of such symptoms












Arthralgia Myalgia





4.9 Overdose



Pharmacotherapeutic group: Proton pump inhibitors ATC Code: A02BC02 Pantoprazole is a substituted benzimidazole, which inhibits gastric juice secretion through specific reactions with proton pumps in the parietal cells. Pantoprazole is converted to its active form in the acidic channel of the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and acts on both basal and stimulated gastric juice secretion. Most patients are symptom-free within 2 weeks. Like with other proton pump inhibitors and H2 receptor blockers, treatment with pantoprazole reduces levels of gastric juice, which causes a rise in gastrin in relation to the acid reduction. The rise in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can affect acid secretion independently of stimulation by other substances (acetylcholine, histamine and gastrin). Pantoprazole has the same effect when administered orally and intravenously.


23

Fasting gastrin levels rise with pantoprazole. If pantoprazole is only used for a short term therapy, it doesn’t usually exceed the upper limit of normal. If pantoprazole is taken over a long period of time, gastrin levels can double. An excessive increase, however, occurs only in isolated cases. With long-term treatment a mild to moderate increase of specific endocrine (ECL = enterochromaffin-like) cells in the stomach occurs in a minority of patients (simple to adenomatoid hyperplasia). However, to date, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids, such as were reported in animal trials (see section 5.3), have not been observed in studies in humans.


General pharmacokinetics Pantoprazole is rapidly absorbed and the maximum serum concentration of around 1 - 1.5 µg/ml is reached after an average of 2.0 – 2.5 hours and remains constant on multiple dosing. The volume of distribution is around 0.15 l/kg, and clearance is around 0.1 l/h/kg. The terminal elimination half-life is about 1 hour though a small number of subjects show slower elimination. Because of the mechanism of binding of pantoprazole to the proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of therapeutic action (inhibition of acid secretion). For both oral and intravenous administration, the pharmacokinetics remain constant after single and multiple dosing and are linear over the dose range 10 – 80 mg. Serum protein binding of pantoprazole is around 98%. Pantoprazole is virtually entirely metabolised by the liver. Most metabolites (around 80 %) are eliminated in the kidneys, and the rest are excreted in faeces. The main metabolite in serum and urine is desmethyl-pantoprazole conjugated with sulphate. The half-life of this main metabolite (about 1.5 h) is not much longer than that of pantoprazole. Bioavailability Pantoprazole is completely absorbed after oral administration. The bioavailability of the tablet being around 77 %. AUC, maximum serum concentration and oral bioavailability are unaffected by food, though lag-time may be increased. Special patient groups No dose reduction is required when pantoprazole is given to patients with reduced kidney function (including dialysis patients) although a daily dose of 40 mg should not be exceeded (see section 4.2). The half-life is not prolonged. Pantoprazole is only dialysed to a very small extent. Although the main metabolite shows a moderately increased half-life (2 – 3 hours), there is no accumulation with this rapid elimination. In patients with liver cirrhosis (Child A and Child B classification) the half-life increases to 3 - 6 hours and the AUC increases by a factor of 3 – 5. However, the maximum serum concentration only increased by a factor of 1.3 compared to in those with normal hepatic function. A relative slight increase of AUC and Cmax in elderly patients is of no clinical relevance.


Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. In a 2-year carcinogenicity study on rats, neuroendocrine tumours were found. Squamous cell papilloma also appeared in the rats’ gastroesophageal vestibule. The mechanism, which is based on stomach carcinoids forming due to substituted benzimidazole, was studied immediately and the conclusion was that it is an indirect mechanism due to the significantly increased serum gastrin level in rats when it is administered chronically and in high doses.


24

A higher rate of liver tumours was observed in rats (only in one study) and female mice in the 2-year studies, which can be interpreted as a consequence of pantoprazole’s high metabolic rate in the liver. In one 2-year study a smaller rise in neoplasms in the rats’ thyroid gland was observed in the highest dose group (200 mg/kg). The appearance of these neoplasms is related to thyroxin being broken down differently in the rats’ liver due to pantoprazole. On the basis of the low therapeutic dose in humans, no side effects on the thyroid glands are expected. From mutagenicity studies, cell transformation tests and a DNA binding study it is concluded that pantoprazole has no genotoxic potential. Tests have revealed no evidence of impaired fertility or teratogenic effects. The placental transfer of pantoprazole was examined in the rats. It increases with progressive pregnancy. Therefore the concentration is elevated in the fetus just before it is born.


Tablet Core: microcrystalline cellulose (E460i) lactose monohydrate croscarmellose sodium colloidal anhydrous silica magnesium stearate Colour coating: polyvinyl alcohol macrogol 3350 titanium dioxide (E171) talc (E553b) iron oxide yellow (E172) quinoline yellow aluminium lake (E104) Gastro-resistant coating: methacryl acid-ethyl acrylate copolymer sodium lauryl sulphate polysorbate 80 triethyl citrate (E1505) talc (E553b)

6.2 Incompatibilities








No special requirements.


25

7 MARKETING AUTHORISATION HOLDER




24/05/2010 10 DATE OF REVISION OF THE TEXT

24/05/2010


26

1 NAME OF THE MEDICINAL PRODUCT Dialoc 40 mg Gastro-resistant tablets


Each gastro-resistant tablet contains 40 mg pantoprazole (as pantoprazole sodium sesquihydrate 45.1 mg) Excipients: Lactose 36.2 mg, tartrazine For a full list of excipients, see section 6.1.


Gastro-resistant tablet Pale yellow to ochre, elongated coated tablet


For relieving the symptoms of, and for the short-term treatment of, gastrointestinal diseases which require a reduction in gastric acid secretion.

• Moderate and severe reflux oesophagitis

• Duodenal ulcer

• Gastric ulcer

• Eradication of Helicobacter pylori, in combination with antibiotic therapy, in patients with peptic ulceration

• Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid.


Method of administration Dialoc 40 mg should be swallowed whole with water before a meal. The tablets should not be chewed or crushed. Adults and adolescents 12 years of age and above Moderate and severe reflux oesophagitis: The recommended dosage is 40 mg pantoprazole daily. In some cases this may be doubled, especially when there has been no response to other treatment. A four-week period is usually required for the treatment of reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further four weeks. Adults Gastric and duodenal ulcer: The recommended dosage is 40 mg pantoprazole daily. In some cases this may be doubled, especially when there has been no response to other treatment. Duodenal ulcers generally heal within two weeks. If a two-week period of treatment is not sufficient, healing will be achieved in almost all cases within a further two weeks. A four week treatment period is usually required for the treatment of gastric ulcers and reflux oesophagitis. If this is not sufficient, healing will usually be achieved within a further four weeks. Eradication of Helicobacter pylori (H. pylori): The recommended dose is 40 mg pantoprazole twice daily, in combination with one of the following three antibiotic regimens: a) Amoxicillin 1000 mg twice daily + clarithromycin 500 mg twice daily. b) Clarithromycin 500 mg twice daily + metronidazole 500 mg twice daily


27

c) Amoxicillin 1000 mg twice daily + metronidazole 500 mg twice daily The second pantoprazole tablet should be taken before the evening meal. Combination therapy should be continued for seven days in most cases but may sometimes be required for up to 14 days. Zollinger-Ellison Syndrome and other hypersecretory conditions: For long-term therapy of Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid, the recommended initial dose is 80 mg (2 tablets Dialoc 40 mg) per day. The dosage can subsequently be adjusted individually according to the determination of gastric acid secretion. For doses of more than 80 mg per day, the dose should be divided and given twice daily. A temporary increase in dose to more than 160 mg pantoprazole per day is possible. However, the increase should only last as long as required to sufficiently control acid secretion. With Zollinger-Ellison syndrome and other diseases associated with a pathological hypersecretion of gastric acid, the period of treatment is not restricted and should continue as long as clinically required. Elderly A daily dose of 40 mg pantoprazole should not be exceeded unless for the eradication treatment of H. pylori in which case a regimen including pantoprazole 40 mg twice daily should be used (see above). Patients with renal impairment A daily dose of 40 mg pantoprazole should not be exceeded. For this reason the H.pylori eradication regimen is not recommended in these patients (see section 4.3). Patients with hepatic impairment The dose should be reduced to 40 mg pantoprazole every other day in patients with severe liver insufficiency and for this reason the H. pylori eradication regimen is not recommended in these patients (see section 4.3). In addition, liver function tests should be monitored in these patients during therapy with Dialoc 40 mg and treatment discontinued if an increase in liver enzymes is observed. Children below 12 years of age There is no experience in the use of pantoprazole in children. Therefore pantoprazole tablets should not be used in children.


Dialoc 40 mg should not be taken under the following circumstances: − Hypersensitivity to pantoprazole or to any of the excipients (see section 6.1)

− in combination therapy for eradication of Helicobacter pylori in patients with moderate to severe hepatic or renal dysfunction, since currently no data is available on the efficacy and safety of pantoprazole in combination treatment of these patients.


− Pantoprazole should not be used in combination therapy for the eradication of H.pylori in patients with moderate to severe hepatic or renal dysfunction since there are currently no relevant efficacy and safety data in relation to this.


Pantoprazole is not intended for the treatment of gastrointestinal symptoms accompanying functional dyspepsia. The Summaries of Product Characteristics for each medication should be observed for combination therapy.


28

For patients with Zollinger-Ellison syndrome and other diseases associated with abnormal overproduction of gastric acid requiring long-term treatment, pantoprazole, as with other acid-blocking drugs, may reduce the absorption of Vitamin B12 (cyanocobalamin) due to hypochlorhydria or achlorhydria. This should be considered in patients on long-term therapy who have reduced B12 body stores or risk factors for reduced vitamin B12 absorption or in those who exhibit signs or symptoms of B12 deficiency. If the patient exhibits worrying signs or symptoms (e.g. significant unintentional weight loss, recurrent vomiting, dysphagia, haematemesis, anaemia or blood in the stool/melena) or if a stomach ulcer is suspected or has been confirmed, malignant disease of the oesophagus or stomach should be excluded. This is because treatment with pantoprazole may mask the symptoms of malignancy and thus delay diagnosis. Diagnoses of peptic oesophagitis should be performed endoscopically. There are no data currently available on the use of pantoprazole in children. Patients with rare hereditary galactose intolerance, lactase deficiency or glucose galactose malabsorption should not take Dialoc 40 mg. This product contains tartrazine, which may cause allergic reactions. This medicinal product contains 2.68 mg sodium per dose. This should be taken into consideration by patients on a controlled sodium diet.


Studies with other proton pump inhibitors have shown that the bioavailability of atazanavir is significantly reduced when it is used concomitantly with proton pump inhibitors. Therefore the use of pantoprazole is contraindicated during atazanavir treatment. Dialoc 40 mg can reduce the absorption of medicines, whose bioavailability is dependent on pH level (e.g. ketoconazole and itraconazole). Pantoprazole is metabolised in the liver by the cytochrome P450 enzyme system. Interaction with other medicines such as substances, which are broken down by the same enzyme system, cannot be ruled out. However, no clinically significant interactions were found in targeted studies with a range of such medicines or compounds, such as carbamazepine, caffeine, diazepam, diclofenac, digoxin, ethanol, glibenclamide, metoprolol, naproxen, nifedipine, phenytoin, piroxicam, theophylline and oral contraceptives. No clinically relevant interactions have been observed in human pharmacokinetic studies with clarithromycin, metronidazole or amoxicillin. Although no interactions were found in clinical pharmacokinetic studies when phenprocoumon or warfarin were taken concomitantly, a few isolated post-marketing reports of changes in prothrombin time / INR have been reported. It is therefore recommended that prothrombin time / INR are monitored in patients being treated with concomitant coumarin anticoagulants after initiation, termination or during irregular use of pantoprazole. There were also no interactions with concomitantly administered antacids.





29

There are no known effects on the ability to drive or use machines. However, uncommon side-effects such as dizziness or blurred vision have been reported (see section 4.8) if affected the patient should refrain from driving or using machines.








Psychiatric disorders Depression, hallucination, disorientation and confusion especially in predisposed patients, as well as the aggravation of such symptoms












Arthralgia Myalgia





4.9 Overdose


30



Pharmacotherapeutic group: Proton pump inhibitors ATC Code: A02BC02 Pantoprazole is a substituted benzimidazole, which inhibits gastric juice secretion through specific reactions with proton pumps in the parietal cells. Pantoprazole is converted to its active form in the acidic channel of the parietal cells where it inhibits the H+, K+-ATPase enzyme, i.e. the final stage in the production of hydrochloric acid in the stomach. The inhibition is dose-dependent and acts on both basal and stimulated gastric juice secretion. Most patients are symptom-free within 2 weeks. Like with other proton pump inhibitors and H2 receptor blockers, treatment with pantoprazole reduces levels of gastric juice, which causes a rise in gastrin in relation to the acid reduction. The rise in gastrin is reversible. Since pantoprazole binds to the enzyme distal to the receptor level, it can affect acid secretion independently of stimulation by other substances (acetylcholine, histamine and gastrin). Pantoprazole has the same effect when administered orally and intravenously. Fasting gastrin levels rise with pantoprazole. If pantoprazole is only used for a short term therapy, it usually doesn’t exceed the upper limit of normal. If pantoprazole is taken over a long period of time, gastrin levels can double. An excessive increase, however, occurs only in isolated cases. With long-term treatment a mild to moderate increase of specific endocrine (ECL = enterochromaffin-like) cells in the stomach occurs in a minority of patients (simple to adenomatoid hyperplasia). However, to date, the formation of carcinoid precursors (atypical hyperplasia) or gastric carcinoids, such as were reported in animal trials (see section 5.3), have not been observed in studies in humans.


General pharmacokinetics Pantoprazole is rapidly absorbed and the maximum serum concentration of around 2-3 µg/ml is reached after an average of 2.0 – 2.5 hours. The volume of distribution is around 0.15 l/kg, and clearance is around 0.1 l/h/kg. The terminal elimination half-life is about 1 hour though a small number of subjects show slower elimination. Because of the mechanism of binding of pantoprazole to the proton pumps of parietal cells, the elimination half-life does not correlate with the much longer duration of therapeutic action (inhibition of acid secretion). For both oral and intravenous administration, the pharmacokinetics remain constant after single and multiple dosing and are linear over the dose range 10 – 80 mg. Serum protein binding of pantoprazole is around 98 %. Pantoprazole is virtually entirely metabolised by the liver. Most metabolites (around 80 %) are eliminated in the kidneys, and the rest are excreted in faeces. The main metabolite in serum and urine is desmethyl-pantoprazole conjugated with sulphate. The half-life of this main metabolite (about 1.5 h) is not much longer than that of pantoprazole. Bioavailability Pantoprazole is completely absorbed after oral administration. The bioavailability of the tablet being around 77 %. AUC, maximum serum concentration and oral bioavailability are unaffected by food, though lag-time may be increased. Special patient groups


31

No dose reduction is required when pantoprazole is given to patients with reduced kidney function (including dialysis patients) although a daily dose of 40 mg should not be exceeded (see section 4.2). The half-life is not prolonged. Pantoprazole is only dialysed to a very small extent. Although the main metabolite shows a moderately increased half-life (2 – 3 hours), there is no accumulation with this rapid elimination. In patients with liver cirrhosis (Child A and Child B classification) the half-life increases to 3 - 6 hours and the AUC increases by a factor of 3 – 5. However, the maximum serum concentration only increased by a factor of 1.3 compared to in those with normal hepatic function. A relative slight increase of AUC and Cmax in elderly patients is of no clinical relevance.


Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction. In a 2-year carcinogenicity study on rats, neuroendocrine tumours were found. Squamous cell papilloma also appeared in the rats’ gastroesophageal vestibule. The mechanism, which is based on stomach carcinoids forming due to substituted benzimidazole, was studied immediately and the conclusion was that it is an indirect mechanism due to the significantly increased serum gastrin level in rats when it is administered chronically and in high doses. A higher rate of liver tumours was observed in rats (only in one study) and female mice in the 2-year studies, which can be interpreted as a consequence of pantoprazole’s high metabolic rate in the liver. In one 2-year study a smaller rise in neoplasms in the rats’ thyroid gland was observed in the highest dose group (200 mg/kg). The appearance of these neoplasms is related to thyroxin being broken down differently in the rats’ liver due to pantoprazole. On the basis of the low therapeutic dose in humans, no side effects on the thyroid glands are expected. From mutagenicity studies, cell transformation tests and a DNA binding study it is concluded that pantoprazole has no genotoxic potential. Tests have revealed no evidence of impaired fertility or teratogenic effects. The placental transfer of pantoprazole was examined in the rats. It increases with progressive pregnancy. Therefore the concentration is elevated in the fetus just before it is born.


Tablet Core: microcrystalline cellulose (E460i) lactose monohydrate croscarmellose sodium colloidal anhydrous silica magnesium stearate Colour coating: polyvinyl alcohol macrogol 3350 titanium dioxide (E171) talc (E553b) iron oxide yellow (E172) tartrazine aluminium lake (E102) Gastro-resistant coating: methacryl acid-ethyl acrylate copolymer sodium lauryl sulphate polysorbate 80 triethyl citrate (E1505)


32

talc (E553b) 6.2 Incompatibilities







6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER




24/05/2010

10 DATE OF REVISION OF THE TEXT 24/05/2010


33

Module 3 PACKAGE LEAFLET: INFORMATION FOR THE USER


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Module 5 Scientific discussion during initial procedure

I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considers that the applications for:

• Pantodia/Dialoc 20 mg Gastro-resistant Tablets for the management of mild reflux disease and prevention of gastroduodenal ulceration

And • Pantodia/Dialoc 40mg Gastro-resistant Tablets, for the treatment of peptic

ulceration, moderate to severe reflux oesophagitis, hypersecretory conditions including Zollinger-Ellison Syndrome and, in combination with appropriate antibiotic therapy, eradication of Helicobacter pylori infection in patients with peptic ulceration

Could be approved. These are applications made under the decentralised procedure (DCP), according to Article 10.1 of Directive 2001/83, as amended, claiming to be generic medicinal products of Pantoloc 40mg Gastro-resistant Tablet, which were originally granted licences to Nycomed Pharma GmbH (Austria) on 29th June 1995. The corresponding medicinal products which are authorised in the RMS are Protium 20mg and 40mg gastro-resistant tablets (Nycomed GmbH). The UK is the Reference Member State (RMS) in these Decentralised Procedures, and the Concerned Member States (CMS) are: Poland, Romania, and Slovenia (UK/H/1802/01-02/DC) Austria, Belgium, Denmark, Finland, The Netherlands, Norway, Poland and Sweden (UK/H/1803/01-02/DC) Pantodia/Dialoc is a proton pump inhibitor, i.e. it inhibits the gastric H+/K+-ATPase enzyme, which is responsible for acid secretion in the parietal cells of the stomach. The action is specific and dose-proportional. It is used for the treatment of acid related disease like upper gastrointestinal ulceration and oesophageal reflux disease and (in conjunction with antibiotics) the eradication of Helicobacter pylori. No new preclinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products that have been licensed for over 10 years. No new clinical studies were conducted, which is acceptable given that the applications were based on being generic medicinal products of originator products that have been licensed for over 10 years. The bioequivalence study was carried out in accordance with Good Clinical practice (GCP). The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture, assembly and batch release


74

of these products. The RMS and CMS considered that the applications could be approved with the end of procedure (Day 210) on 21st April 2010. The licences were granted in the UK on 24th May 2010.


75

II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Pantodia/Dialoc 20mg and 40mg Gastro-resistant Tablets

Name(s) of the active substance(s) (INN) Pantoprazole sodium sesquihydrate Pharmacotherapeutic classification (ATC code)

Proton Pump Inhibitor (A02BC02)

Pharmaceutical form and strength(s) Gastro-resistant Tablets Reference numbers for the Mutual Recognition Procedure

UK/H/1802-3/01-02/DC

Reference Member State United Kingdom Member States Concerned UK/H/1802/01-02/DC: Poland, Romania, and

Slovenia UK/H/1803/01-02/DC: Austria, Belgium, Denmark, Finland, The Netherlands, Norway, Poland and Sweden

Marketing Authorisation Number(s) PL 32652/0001-4 Name and address of the authorisation holder

DiaMed GmbH, Kaiser-Wilhelm-ring 4-6, 48145 Munster, Germany


76

III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. DRUG SUBSTANCE INN: Pantoprazole sodium sesquihydrate Chemical Name: 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl]methyl]sulphinyl] -1H-benzimidazole sodium salt sesquihydrate Structure:

Molecular Formula: C16H14F2N3NaO4S.3/2H2O Molecular Weight: 432.38g.mol Appearance: White to off-white powder. It is freely soluble in water, methanol and ethanol (96%), practically insoluble in hexane. All aspects of the manufacture and control of the active substance pantoprazole sodium sesquihydrate are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability. P. DRUG PRODUCT Other ingredients Other ingredients consist of the pharmaceutical excipients microcrystalline cellulose (E460i), lactose monohydrate, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, Opadry II 85F32081 Yellow (polyvinyl alcohol, macrogol 3350, titanium dioxide (E171), iron oxide yellow (E172), quinoline yellow aluminium lake (E104), sodium lauryl sulphate, polysorbate 80), methacryl acid-ethyl acrylate copolymer, triethyl citrate (E1505) and talc (E553b)

All excipients comply with their respective European Pharmacopoeia monographs with the exception of Opadry II 85F32081 Yellow which complies with an in-house specification. Satisfactory Certificates of Analysis have been provided for all excipients. With the exception of lactose monohydrate and calcium stearate, none of the excipients are sourced from animal or human origin. The suppliers of lactose monohydrate has confirmed that it is sourced from healthy animals, under the same conditions as milk for human consumption and the calcium stearate is sourced from vegetable. No genetically modified organisms (GMO) have been used in the preparation of these products. Pharmaceutical Development The objective of the development programme was to formulate robust, stable tablets that were containing qualitatively and quantitatively the same active ingredient as


77

Pantoloc Gastro-resistant Tablets (Nycomed Pharma GmbH, Austria), and exhibiting the same bioavailability in order to comply with the regulations pertaining to generic medicinal product applications. A satisfactory account of the pharmaceutical development has been provided. Comparative in vitro dissolution and impurity profiles have been provided for the proposed and originator products. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory, based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results are satisfactory. Finished product specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of Analysis have been provided for any working standards used.

Container-Closure System All strengths of tablets are packaged in either 1. aluminium-aluminium foil blisters in pack sizes of 7, 14, 28 or 56 gastro-

resistant tablets or 2. HDPE bottles with HDPE or PP screw cap closure with desiccant, in pack sizes of 7, 14, 28 or 50 gastro-resistant tablets. The marketing authorisation holder has stated that they do not intend to market all pack sizes for all product licences at the present time. However, they have committed to submitting mock-ups for any pack sizes to the regulatory authorities for approval before marketing. Satisfactory specifications and certificates of analysis have been provided for all packaging components. All primary packaging complies with the current European regulations concerning materials in contact with food. Stability Finished product stability studies have been conducted in accordance with current guidelines and in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years with a storage condition ‘Do not store above 30°C’ is set for the blister packs and 3 years with a storage condition of ‘Do not store above 25°C’ is set for the bottles. These are acceptable. Bioequivalence/bioavailability Satisfactory Certificates of Analysis have been provided for the test and reference batches used in the bioequivalence study. SPC, PIL, Labels


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The SPC, PIL and labels are pharmaceutically acceptable. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. Pharmacovigilance System and Risk Management Plan The pharmacovigilance system, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance, and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. A suitable justification has been provided for not submitting a risk management plan for these products. MAA forms The MAA forms are pharmaceutically satisfactory. Expert report The pharmaceutical expert report has been written by an appropriately qualified person and is a suitable summary of the pharmaceutical dossier. Conclusion The grant of marketing authorisation is recommended III.2 PRE-CLINICAL ASPECTS As the pharmacodynamic, pharmacokinetic and toxicological properties of pantoprazole sodium sesquihydrate are well-known, no further preclinical studies are required and none have been provided. The applicant’s non-clinical expert report has been written by an appropriately qualified person and is satisfactory, providing an appropriate review of the products’ pharmacology and toxicology. A suitable justification has been provided for non-submission of an environmental risk assessment. There are no objections to the approval of these products from a preclinical viewpoint. III.3 CLINICAL ASPECTS Pharmacokinetics To support these applications the applicant has submitted two bioequivalence studies performed under fasting and fed conditions.


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1. A randomized, single dose, open-label, two period, two-sequence, blinded crossover, comparative bioavailability study on Pantoprazole 40mg gastro-resistant tablets compared with Eupantol 40mg gastro-resistant tablets in 36 healthy, adults, under fasting conditions. Of these, the protocol pre-specified that the first 30 would be analysed; the remaining 6 were reserves to replace possible drop-outs.

2. A randomized, single dose, open-label, two period, two-sequence, blinded

crossover, comparative bioavailability study on Pantoprazole 40mg gastro-resistant tablets compared with Eupantol 40mg gastro-resistant tablets in 36 healthy, adults, under fed conditions. Of these, the protocol pre-specified that the first 30 would be analysed; the remaining 6 were reserves to replace possible drop-outs.

Serial blood samples for plasma pantoprazole assay were taken prior to dosing then at 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 5, 6, 8,10,12, 16 and 24 hours post dose. Each study period was separated by an adequate 7-day washout corresponding to more than 10 times the expected half life of the moiety to be measured. Results Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD) under fasting condition

Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD) under fed condition


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The single dosing studies with the 40mg tablet, under both fed and fasting conditions, show bioequivalence compared to the reference product and results can be extrapolated to the lower strength 20mg tablet, according to conditions in Note for Guidance on the Investigation of Bioavailability and Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4. Pharmacodynamics The pharmacodynamic characteristics of pantoprazole have been well-studied in the past. There would be no particular concerns for a generic medicinal product. Clinical Efficacy No new data have been submitted and none are required. Clinical Safety No new data have been submitted and none are required. SPC, PIL and Labels The SPC, PIL and labels are medically acceptable. The SPCs are consistent with those for the originator products. Expert Reports The clinical expert report has been written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. 6. Conclusion The grant of marketing authorisation is recommended. IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of Pantodia/Dialoc 20mg and 40mg Gastro-resistant Tablets are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY Bioequivalence has been demonstrated between the applicant’s Pantoprazole 40mg Gastro-resistant Tablets and its respective reference product. As the 20mg strength of the product meet the criteria specified in the Notes for Guidance on the Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98) the results and conclusions of the bioequivalence study on the 40mg strength can be extrapolated to the other strength of tablet. No new or unexpected safety concerns arise from these applications.


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The SPC PIL and labelling are satisfactory and consistent with those of the reference products. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. The bioequivalence study supports the claim that the applicants’ products and the originator products are interchangeable. Extensive clinical experience with pantoprazole is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

public assessment report pantodia 20mg and 40 mg gastro

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